Background 99mTc-Tilmanocept is a radiopharmaceutical currently used in humans to facilitate preoperative lymphoscintigraphy and more accurate intraoperative lymphatic mapping with discrete sentinel node detection (SLN) of solid tumors. This SLN target specificity is the result, in part, of 99mTc-Tilmanocept binding to CD206 on tumor-associated macrophages. CD206 is a mannose-binding receptor that is highly expressed by alternatively activated macrophages.
Objectives Using a fluorescently-labeled derivative of 99mTc-Tilmanocept, Manocept-Cy3, we examined the potential efficacy of this pharmaceutical in rheumatoid arthritis (RA). Identification of CD206 positive macrophages in RA would enable theranostic application of Manocept as an early diagnostic and in therapeutic monitoring, and also as a therapeutic platform for drug delivery.
Methods Synovial fluid and tissue were acquired from RA patients for comparison to normal frozen archival tissue and synovial tissue procured from patients with osteoarthritis (OA). Tissues were probed with Manocept-Cy3 (red), DAPI nuclear stain (blue), and anti CD206-cyanine green. Mononuclear cells were isolated from RA synovial fluid and analyzed by flow cytometry. Arthritis was induced in Dba1 mice with anti-cartilage monoclonal antibodies followed by injection with E. coli LPS. Manocept-Cy3 was injected intravenously and epifluorescent imaging was conducted.
Results Immunohistochemistry (IHC) of synovial tissue from RA patients showed significantly greater fluorescent detection of cellular Manocept-Cy3 signals relative to healthy control and OA tissue, which displayed little to no fluorescence. This RA tissue also demonstrated CD206 and Manocept-Cy3 co-localization. To confirm macrophage specific labeling, flow cytometry was performed on RA synovial fluid and positive detection was observed in conjunction with CD14, CD16, CD11b, and CD163. Feasibility of Manocept as a diagnostic imaging agent in RA was subsequently evaluated in an animal model; epifluorescent imaging ex vivo and in vivo indicated significantly greater signals in both the knees and elbows of arthritic mice.
Conclusions The results of this study: i) indicate that alternatively activated macrophages expressing CD206 are novel biomarkers of RA inflammation and ii) suggest that Manocept is a viable candidate to pursue clinically as an imaging biomarker for disease activity in RA patients by labeling inflammatory macrophages in inflamed joints. The versatility of the Manocept backbone will be a focus of future congener development using additional reporter types to exploit CD206 in RA, including therapeutics to modulate the inflammatory response.
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Acknowledgements Funding for this work was provided through the Wexner Medical Center at The Ohio State University.
Disclosure of Interest None declared
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